Myron Chang

Novel prognostic subgroups in childhood 11q23/MLL-rearranged acute myeloid leukemia: results of an international retrospective study

Translocations involving chromosome 11q23 frequently occur in pediatric acute myeloid leukemia (AML) and are associated with poor prognosis. In most cases, the MLL gene is involved, and more than 50 translocation partners have been described. Clinical outcome data of the 11q23-rearranged subgroups are scarce because most 11q23 series are too small for meaningful analysis of subgroups, although some studies suggest that patients with t(9;11)(p22;q23) have a more favorable prognosis. We retrospectively collected outcome data of 756 children with 11q23- or MLL-rearranged AML from 11 collaborative groups to identify differences in outcome based on translocation partners. All karyotypes were centrally reviewed before assigning patients to subgroups. The event-free survival of 11q23/MLL-rearranged pediatric AML at 5 years from diagnosis was 44% (+/- 5%), with large differences across subgroups (11% +/- 5% to 92% +/- 5%). Multivariate analysis identified the following subgroups as independent prognostic predictors: t(1;11)(q21;q23) (hazard ratio [HR] = 0.1, P = .004); t(6;11)(q27;q23) (HR = 2.2, P < .001); t(10;11)(p12;q23) (HR = 1.5, P = .005); and t(10;11)(p11.2;q23) (HR = 2.5, P = .005). We could not confirm the favorable prognosis of the t(9;11)(p22;q23) subgroup. We identified large differences in outcome within 11q23/MLL-rearranged pediatric AML and novel subgroups based on translocation partners that independently predict clinical outcome. Screening for these translocation partners is needed for accurate treatment stratification at diagnosis.

Pediatric Oncology Group (POG) studies of acute myeloid leukemia (AML): a review of four consecutive childhood AML trials conducted between 1981 and 2000.

From 1981 to 2000, a total of 1823 children with acute myeloid leukemia (AML) enrolled on four consecutive Pediatric Oncology Group (POG) clinical trials. POG 8101 demonstrated that the induction rate associated with the 3+7+7 combination of daunorubicin, Ara-C, and 6-thioguanine (DAT) was greater than that associated with an induction regimen used to treat acute lymphoblastic leukemia (82 vs 61%; P=0.02). Designed as a pilot study to determine the feasibility of administration of noncross-resistant drug pairs and later modified to assess the effect of dose intensification of Ara-C during the second induction course, POG 8498 confirmed the high initial rate of response to DAT (84.2%) and showed that dose intensification of Ara-C during the second induction course resulted in a trend toward higher event-free survival (EFS) estimates than did standard-dose DAT (2+5) during the second induction course (5 year EFS estimates, 22 vs 27%; P=0.33). Age <2 years and leukocyte count <100 000/mm3 emerged as significantly good prognostic factors. The most significant observation made in the POG 8498 study was the markedly superior outcome of children with Downs syndrome who were treated on the high-dose Ara-C regimen. POG 8821 compared the efficacy of autologous bone marrow transplantation (BMT) with that of intensive consolidation chemotherapy. Intent-to-treat analysis revealed similar 5-year EFS estimates for the group that underwent autologous BMT (36±4.7%) and for the group that received only intensive chemotherapy (35±4.5%) (P=0.25). There was a high rate of treatment-related mortality in the autologous transplantation group. The study demonstrated superior results of allogeneic BMT for patients with histocompatible related donors (5-year EFS estimate 63±5.4%) and of children with Downs syndrome (5-year EFS estimate, 66±8.6%). The POG 9421 AML study evaluated high-dose Ara-C as part of the first induction course and the use of the multidrug resistance modulator cyclosporine. Preliminary results showed that patients receiving both high-dose Ara-C for remission induction and the MDR modulator for consolidation had a superior outcome (5-year EFS estimate, 42±8.2%) than did patients receiving other treatment; however, the difference was not statistically significant. These four studies demonstrate the importance of dose intensification of Ara-C in the treatment of childhood AML; cytogenetics as the single most prognostic factor and the unique curability of AML in children with Downs syndrome.

Prevalence and prognostic significance of KIT mutations in pediatric patients with core binding factor AML enrolled on serial pediatric cooperative trials for de novo AML.

KIT receptor tyrosine kinase mutations are implicated as a prognostic factor in adults with core binding factor (CBF) acute myeloid leukemia (AML). However, their prevalence and prognostic significance in pediatric CBF AML is not well established. We performed KIT mutational analysis (exon 8 and exon 17) on diagnostic specimens from 203 pediatric patients with CBF AML enrolled on 4 pediatric AML protocols. KIT mutations were detected in 38 (19%) of 203 (95% CI, 14%-25%) patient samples of which 20 (52.5%) of 38 (95% CI, 36%-69%) involved exon 8, 17 (45%) of 38 (95% CI, 29%-62%) involved exon 17, and 1 (2.5%; 95% CI, 0%-14%) involved both locations. Patients with KIT mutations had a 5-year event-free survival of 55% (+/- 17%) compared with 59% (+/- 9%) for patients with wild-type KIT (P = .86). Rates of complete remission, overall survival, disease-free survival, or relapse were not significantly different for patients with or without KIT mutations. Location of the KIT mutation and analysis by cytogenetic subtype [t(8;21) vs inv(16)] also lacked prognostic significance. Our study shows that KIT mutations lack prognostic significance in a large series of pediatric patients with CBF AML. This finding, which differs from adult series and a previously published pediatric study, may reflect variations in therapeutic approaches and/or biologic heterogeneity within CBF AML. Two of 4 studies included in this analysis are registered at http://clinicaltrials.gov as NCT00002798 (CCG-2961) and NCT00070174 (COG AAML03P1).

A study of rituximab and ifosfamide, carboplatin, and etoposide chemotherapy in children with recurrent/refractory B-cell (CD20+) non-Hodgkin lymphoma and mature B-cell acute lymphoblastic leukemia: A report from the Children's Oncology Group

To estimate the response rate and therapy related toxicities of the anti‐CD20 monoclonal antibody rituximab when combined with chemotherapy including ifosfamide, carboplatin, and etoposide (ICE) in patients with relapsed and refractory B‐cell non‐Hodgkin lymphoma and mature B‐cell acute lymphoblastic leukemia (B‐ALL).

Prognostic factors in children and adolescents with acute myeloid leukemia (excluding children with Down syndrome and acute promyelocytic leukemia): univariate and recursive partitioning analysis of patients treated on Pediatric Oncology Group (POG) Study 8821

The purpose of the paper was to define clinical or biological features associated with the risk for treatment failure for children with acute myeloid leukemia. Data from 560 children and adolescents with newly diagnosed acute myeloid leukemia who entered the Pediatric Oncology Group Study 8821 from June 1988 to March 1993 were analyzed by univariate and recursive partitioning methods. Children with Down syndrome or acute promyelocytic leukemia were excluded from the study. Factors examined included age, number of leukocytes, sex, FAB morphologic subtype, cytogenetic findings, and extramedullary disease at the time of diagnosis. The overall event-free survival (EFS) rate at 4 years was 32.7% (s.e. = 2.2%). Age ⩾2 years, fewer than 50 × 109/l leukocytes, and t(8;21) or inv(16), and normal chromosomes were associated with higher rates of EFS (P value = 0.003, 0.049, 0.0003, 0.031, respectively), whereas the M5 subtype of AML (P value = 0.0003) and chromosome abnormalities other than t(8;21) and inv(16) were associated with lower rates of EFS (Pvalue = 0.0001). Recursive partitioning analysis defined three groups of patients with widely varied prognoses: female patients with t(8;21), inv(16), or a normal karyotype (n = 89) had the best prognosis (4-year EFS = 55.1%, s.e. = 5.7%); male patients with t(8;21), inv(16) or normal chromosomes (n = 106) had an intermediate prognosis (4-year EFS = 38.1%, s.e. = 5.3%); patients with chromosome abnormalities other than t(8;21) and inv(16) (n = 233) had the worst prognosis (4-year EFS = 27.0%, s.e. = 3.2%). One hundred and thirty-two patients (24%) could not be grouped because of missing cytogenetic data, mainly due to inadequate marrow samples. The results suggest that pediatric patients with acute myeloid leukemia can be categorized into three potential risk groups for prognosis and that differences in sex and chromosomal abnormalities are associated with differences in estimates of EFS. These results are tentative and must be confirmed by a large prospective clinical trial.

Cardiomyopathy in Children With Down Syndrome Treated for Acute Myeloid Leukemia: A Report From the Children's Oncology Group Study POG 9421

PURPOSE To determine the outcomes, with particular attention to toxicity, of children with Down syndrome (DS) and acute myeloid leukemia (AML) treated on Pediatric Oncology Group (POG) protocol 9421. PATIENTS AND METHODS Children with DS and newly diagnosed AML (n = 57) were prospectively enrolled onto the standard-therapy arm of POG 9421 and were administered five cycles of chemotherapy, which included daunorubicin 135 mg/m(2) and mitoxantrone 80 mg/m(2). Outcomes and toxicity were evaluated prospectively and were compared with the non-DS-AML cohort (n = 565). A retrospective chart review was performed to identify adverse cardiac events. RESULTS In the DS-AML group, 54 patients (94.7%) entered remission. One experienced induction failure and two died. Of the 54 who entered remission, three relapsed and six died as a result of other causes. The remission induction rate was similar in the non-DS-French-American-British (FAB) M7 (91.7%) and non-DS-non-M7 (89.3%) groups. The 5-year overall survival was significantly better in the DS-AML group (78.6%) than in the non-DS-M7 (36.3%) or the non-DS-non-M7 (51.8%) groups (P < .001). No age-related difference in 5-year, event-free survival was seen between patients younger than 2 years (75.8%) and those aged 2 to 4 years (78.3%). Symptomatic cardiomyopathy developed in 10 patients (17.5%) with DS-AML during or soon after completion of treatment; three died as a result of congestive heart failure. CONCLUSION The POG 9421 treatment regimen was highly effective in both remission induction and disease-free survival for patients with DS-AML. However, there was a high incidence of cardiomyopathy, which supports current strategies for dose reduction of anthracyclines in this patient population.

Pharmacokinetic interactions of cyclosporine with etoposide and mitoxantrone in children with acute myeloid leukemia

The purpose of this study was to assess the effect of the multidrug resistance modulator cyclosporine (CsA) on the pharmacokinetics of etoposide and mitoxantrone in children with de novo acute myeloid leukemia (AML). Serial blood samples for pharmacokinetic studies were obtained in 38 children over a 24-h period following cytotoxin treatment with or without CsA on days 1 and 4. Drug concentrations were quantitated using validated HPLC methods, and pharmacokinetic parameters were determined using compartmental modeling with an iterative two-stage approach, implemented on ADAPT II software. Etoposide displayed a greater degree of interindividual variability in clearance and systemic exposure than mitoxantrone. With CsA treatment, etoposide and mitoxantrone mean clearance declined by 71% and 42%, respectively. These effects on clearance, in combination with the empiric 40% dose reduction for either cytotoxin, resulted in a 47% and 12% increases in the mean AUC for etoposide and mitoxantrone, respectively. There were no differences in the rates of stomatitis or infection between the two groups. CsA treatment resulted in an increased incidence of hyperbilrubinemia, which rapidly reversed upon conclusion of drug therapy. The variability observed in clearance, combined with the empiric 40% dose reduction of the cytotoxins, resulted in statistically similar systemic exposure and similar toxicity.

Higher dose imatinib for children with de novo chronic phase chronic myelogenous leukemia: A report from the Children's Oncology Group†‡

To determine the efficacy of imatinib in children with newly diagnosed chronic phase (CP) chronic myelogenous leukemia (CML).

Phase I study of valspodar (PSC-833) with mitoxantrone and etoposide in refractory and relapsed pediatric acute leukemia: a report from the Children's Oncology Group.

Valspodar, a non‐immunosuppressive analog of cylosporine, is a potent P‐glycoprotein (MDR1) inhibitor. As MDR1‐mediated efflux of chemotherapeutic agents from leukemic blasts may contribute to drug resistance, a phase 1 study of valspodar combined with mitoxantrone and etoposide in pediatric patients with relapsed or refractory leukemias was performed.

CD36 (thrombospondin receptor) expression in childhood acute megakaryoblastic leukemia: In vitro drug sensitivity and outcome

The outcome for children with acute megakaryoblastic leukemia (AMKL) remains poor, except for cases associated with Down syndrome (DS). This study compared immunophenotypic and drug sensitivity patterns of childhood AMKL cases with or without DS. All DS-AMKL cases showed high expression of CD36 and were very sensitive to cytarabine and daunorubicin in vitro. In children without DS, high expression of CD36 on AMKL blasts identified a sub-group with immunophenotypic and drug sensitivity patterns similar to that of DS AMKL. Among non-DS AMKL patients, CD36-high cases had a superior outcome compared with CD36-negative cases. CD36 expression in acute myeloid leukemia cases other than AMKL was not associated with increased in vitro drug sensitivity. CD36 expression in AMKL may be an indicator of megakaryoblast maturation and chemotherapy sensitivity.